Tricyclic heterocyclic compounds as 5-HT4 receptor antagonists

ABSTRACT

Compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1  --(CH 2 ) x  --X 2  and the aromatic carbon atoms to which they are attached form 5-7 membered ring wherein X 1  is O or S; X 2  is O, S, NR 5  or NR 6  CO wherein R 5  is hydrogen or C 1-6  alkyl; or one of X 1  and X 2  is O, S or CH 2  and the other is CH 2  ; x is 1, 2 or 3; R 1  and R 2  together are Q--CH 2  --CH 2 , Q--CH═CH, or Q--CH═N where Q is linked either to the R 1  or the R 2  substitution position and Q is O, S or NR t  wherein R t  is hydrogen or C 1-6  alkyl; R 3  is hydrogen halo, C 1-6  alkyl, C 1-6  alkoxy or amino; R 4   1  and R 4   2  are independently hydrogen or C 1-6  alkyl; Y is O or NH; Z is of sub-formula (a), (b) or (c) and their use as pharmaceuticals in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders. ##STR1##

This application is a 371 of PCT/GB94/00172, Jan. 28, 1994.

This invention relates to novel compounds having pharmacologicalactivity, to a process for their preparation and to their use aspharmaceuticals.

European Journal of Pharmacology 146 (1988), 187-188, andNaunyn-Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410, describe anon classical 5-hydroxytryptamine receptor, now designated the 5-HT₄receptor, and that ICS 205-930, which is also a 5-HT₃ receptorantagonist, acts as an antagonist at this receptor.

WO 91/16045 (SmithKline and French Laboratories Limited) describes theuse of cardiac 5-HT₄ receptor antagonists in the treatment of atrialarrhythmias and stroke.

EP-A-501322 (Glaxo Group Limited), WO 93/02677, WO 93/03725, WO93/05038, WO 93/05040, WO 93/18036, and PCT/EP93/03054 (SmithKlineBeecham plc) describe compounds having 5-HT₄ receptor antagonistactivity.

It has now been discovered that certain novel compounds also have 5-HT₄receptor antagonist properties.

EP-A-234872 (Adria), U.S. Pat. No. 4,859,683 (Rorer) and EP-A-307 172(Lilly) describe 5-HT₃ receptor antagonists derived from a benzoic acidnucleus, 2,3-disubstituted by alkyleneoxy.

A class of novel, structurally distinct compounds has now beendiscovered, which compounds are fused tricyclic derivativesincorporating and linking through a core which is a phenyl ring. Thesecompounds have 5-HT₄ receptor antagonist activity.

Accordingly, the present invention provides a compound of formula (I),or a pharmaceutically acceptable salt thereof: ##STR2## wherein in whichX₁ --(CH₂)_(x) --X₂ and the aromatic carbon atoms to which they areattached form a 5-7 membered ring

wherein

X₁ is O or S; X₂ is O, S, NR_(s) or NR_(s) CO wherein R_(s) is hydrogenor C₁₋₆ alkyl; or

one of X₁ and X₂ is O, S or CH₂ and the other is CH₂ ;

x is 1, 2 or 3;

R₁ and R₂ together are Q--CH₂ --CH₂, Q--CH═CH, or Q--CH═N where Q islinked either to the R₁ or the R₂ substitution position and Q is O, S orNR_(t) wherein R_(t) is hydrogen or C₁₋₆ alkyl;

R₃ is hydrogen, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy or amino;

R₄ ¹ and R₄ ² are independently hydrogen or C₁₋₆ alkyl;

Y is O or NH;

Z is of sub-formula (a), (b) or (c): ##STR3## wherein n¹ is 1, 2, 3 or4; n² is 0, 1, 2, 3 or 4; n³ is 2, 3, 4 or 5;

q is 0, 1, 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2;

R₅ is hydrogen, C₁₋₁₂ alkyl, aralkyl or R₅ is (CH₂)_(z) --R₁₀ wherein zis 2 or 3 and R₁₀ is selected from cyano, hydroxyl, C₁₋₆ alkoxy,phenoxy, C(O)C₁₋₆ alkyl, COC₆ H₅, --CONR₁₁ R₁₂, NR₁₁ COR₁₂, SO₂ NR₁₁ R₁₂or NR₁₁ SO₂ R₁₂ wherein R₁₁ and R₁₂ are hydrogen or C₁₋₆ alkyl; or R₅ isstraight or branched chain alkylene of chain length 1-6 carbon atomsterminally substituted by aryl, 3 to 8 membered cycloalkyl, 3 to 8membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl or 9 or 10membered fused bicyclic heteroaryl linked through carbon, C₂₋₇alkoxycarbonyl, or secondary or tertiary hydroxy substituted C₁₋₆ alkyl;and

R₆, R₇ and R₈ are independently hydrogen or C₁₋₆ alkyl; and

R₉ is hydrogen or C₁₋₁₀ alkyl;

or a compound of formula (I) wherein the CO--Y linkage is replaced by aheterocyclic bioisostere;

having 5-HT₄ receptor antagonist activity.

Examples of alkyl or alkyl containing groups include C₁, C₂, C₃, C₄, C₅,C₆, C₇, C₈, C₉, C₁₀, C₁₁ or C₁₂ branched, straight chained or cyclicalkyl, as appropriate. C₁₋₄ alkyl groups include methyl, ethyl, n- andiso-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

Aryl includes phenyl and naphthyl optionally substituted by one or moresubstituents selected from halo, C₁₋₆ alkyl and C₁₋₆ alkoxy.

Values for monocyclic heteroaryl include pyridyl, pyrimidyl, pyrazinyl,pyrryl, imidazolyl, thienyl, furanyl, oxazole or thiazole (all possibleisomers). Bicyclic heteroaryl include benzofuranyl, benzothiophenyl,indolyl and indazolyl, quinolyl and isoquinolyl (all possible isomers).

Values for 3 to 8 membered heterocyclyl, include cyclic polymethyleneinterrupted by one or two of N, O or S, linked through C or N, forexample N-linked piperidinyl or pyrrolidinyl.

Halo includes fluoro, chloro, bromo and iodo.

A suitable bioisostere for the amide or ester linkage containing Y informula (I), is of formula (d): ##STR4## wherein the dotted circlerepresents one or two double bonds in any position in the 5-memberedring; H, J and I independently represent oxygen, sulphur, nitrogen orcarbon, provided that at least one of H, J and I is other than carbon; Urepresents nitrogen or carbon.

Suitable examples of (d) are as described for X, Y and Z in EP-A-328200(Merck Sharp & Dohme Ltd.), such as an oxadiazole moiety.

A suitable value of Q is NR, such as NH.

Suitable examples of the X₁ --(CH₂)_(x) --X₂ moiety include O--(CH₂)₂--O, O--(CH₂)₃ --O, O--CH₂ --O, O--(CH₂)₂ --NR₄, O--(CH₂)₂ --S or O--CH₂--CONR₄, wherein any of the methylene linkages are optionally mono- ordi- substituted by C₁₋₆ alkyl groups, such as methyl. Preferably such X₁--(CH₂)₂ --X₂ is O--(CH₂)₂ --O.

Further suitable examples of the X₁ --(CH₂)_(x) --X₂ include O--(CH₂)₂--CH₂, O--(CH₂)₃ --CH₂, O--CH₂ --CH₂, or corresponding values wherein X₁=X₂ =CH₂, wherein any of the methylene linkages are optionally mono- ordi-substituted by C₁₋₆ alkyl groups, such as methyl. Preferably such X₁--(CH₂)₂ --X₂ is O--(CH₂)₂ --CH₂.

R₄ and R₅ are often hydrogen. When R₄ /R₅ is C₁₋₆ alkyl, it is oftenmethyl. In particular R₄ and R₅ are methyl such that the disubstituentcontaining X₁ and X₂ is O--C(CH₃)₂ --O.

R₃ is preferably hydrogen.

Y is preferably O or NH.

When Z is of sub-formula (a), n¹ is preferably 2, 3 or 4 when theazacycle is attached at the nitrogen atom and n¹ is preferably 1 whenthe azacycle is attached at a carbon atom, such as the 4-position when qis 2.

When Z is of sub-formula (b), n² is preferably such that the number ofcarbon atoms between the ester or amide linkage is from 2 to 4 carbonatoms.

Suitable values for p and m include p=m=1; p=0, m=1, p=1, m=2, p=2, m=1.

When Z is of sub-formula (c), n³ is preferably 2, 3 or 4.

R₈ and R₉ are preferably both alkyl, especially one of R₈ and R₉ is C₄or larger alkyl.

Specific values of Z of particular interest are as follows: ##STR5## Theinvention also provides novel compounds within formula (I) with sidechains (i), (ii), (iii), (iv), (v), (vi) or (vii). In a further aspect,the piperidine ring in (i), (ii) or (iii) may be replaced bypyrrolidinyl or azetidinyl, and/or the N-substituent in (i) or (ii) maybe replaced by C₃ or larger alkyl or optionally substituted benzyl.

In an alternative aspect, the N-substituent in formula (i) or (ii) maybe replaced by (CH₂)_(n) R⁴ as defined in formula (I) and in relation tothe specific examples of EP-A-501322, or it may be replaced by asubstituent

The pharmaceutically acceptable salts of the compounds of the formula(I) include acid addition salts with conventional acids such ashydrochloric, hydrobromic, boric, phosphoric, sulphuric acids andpharmaceutically acceptable organic acids such as acetic, tartaric,maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-ketoglutaric, α-glycerophosphoric, and glucose-1-phosphoric acids.

Examples of pharmaceutically acceptable salts include quaternaryderivatives of the compounds of formula (I) such as the compoundsquaternised by compounds R_(x) --T wherein R_(x) is C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl or C₅₋₇ cycloalkyl, and T is a radical correspondingto an anion of an acid. Suitable examples of R_(x) include methyl, ethyland n- and iso-propyl; and benzyl and phenethyl. Suitable examples of Tinclude halide such as chloride, bromide and iodide.

Examples of pharmaceutically acceptable salts also include internalsalts such as N-oxides.

The compounds of the formula (I), their pharmaceutically acceptablesalts, (including quaternary derivatives and N-oxides) may also formpharmaceutically acceptable solvates, such as hydrates, which areincluded wherever a compound of formula (I) or a salt thereof is hereinreferred to.

It will also be realised that the (CH₂)_(n) 2 moiety in compounds offormula (I) wherein Z is (b), may adopt an α or β or configuration withrespect to the fused azabicyclic moiety.

The compounds of formula (I) may be prepared by conventional coupling ofthe X₁ /X₂ moiety with Z. Suitable methods are as described in GB2125398A (Sandoz Limited), GB 1593 146A and EP-A-36269 (Beecham Groupp.l.c.), EP-A-429984 (Nisshin Flour Milling Co.) and EP-A-328200 (MerckSharp & Dohme Limited). Reference is also made to EP-A-501322 (GlaxoGroup Limited).

Aza(bi)cyclic side chain intermediates are known compounds or may beprepared according to the methods described in the aforementioned patentpublications in the name of SmithKline Beecham p.l.c.

The compounds of the present invention are 5-HT₄ receptor antagonistsand it is thus believed may generally be used in the treatment orprophylaxis of gastrointestinal disorders, cardiovascular disorders andCNS disorders.

They are of potential interest in the treatment of irritable bowelsyndrome (IBS), in particular the diarrhoea aspects of IBS, i.e., thesecompounds block the ability of 5-HT to stimulate gut motility viaactivation of enteric neurones. In animal models of IBS, this can beconveniently measured as a reduction of the rate of defaecation. Theyare also of potential use in the treatment of urinary incontinence whichis often associated with IBS.

They may also be of potential use in other gastrointestinal disorders,such as those associated with upper gut motility, and as antiemetics. Inparticular, they are of potential use in the treatment of the nausea andgastric symptoms of gastro-oesophageal reflux disease and dyspepsia.Antiemetic activity is determined in known animal models ofcytotoxic-agent/radiation induced emesis.

Specific cardiac 5-HT₄ receptor antagonists which prevent atrialfibrillation and other atrial arrhythmias associated with 5-HT, wouldalso be expected to reduce occurrence of stroke (see A. J. Kaumann 1990,Naumyn-Schmiedeberg's Arch. Pharmacol. 342, 619-622, for appropriateanimal test method).

Anxiolytic activity is likely to be effected via the hippocampus (Dumuiset al 1988, Mol Pharmacol., 34, 880-887). Activity can be demonstratedin standard animal models, the social interaction test and the X-mazetest.

Migraine sufferers often undergo situations of anxiety and emotionalstress that precede the appearance of headache (Sachs, 1985, Migraine,Pan Books, London). It has also been observed that during and within 48hours of a migraine attack, cyclic AMP levels are considerably increasedin the cerebrospinal fluid (Welch et al., 1976, Headache 16, 160-167).It is believed that a migraine, including the prodomal phase and theassociated increased levels of cyclic AMP are related to stimulation of5-HT₄ receptors, and hence that administration of a 5-HT₄ antagonist isof potential benefit in relieving a migraine attack.

Other CNS disorders of interest include schizophrenia, Parkinson'sdisease and Huntingdon's chorea.

The invention also provides a pharmaceutical composition comprising acompound of formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

Such compositions are prepared by admixture and are usually adapted forenteral such as oral, nasal or rectal, or parenteral administration, andas such may be in the form of tablets, capsules, oral liquidpreparations, powders, granules, lozenges, reconstitutable powders,nasal sprays, suppositories, injectable and infusable solutions orsuspensions. Orally administrable compositions are preferred, since theyare more convenient for general use.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents, lubricants, disintegrants,colourants, flavourings, and wetting agents. The tablets may be coatedaccording to well known methods in the art, for example with an entericcoating.

Suitable fillers for use include cellulose, mannitol, lactose and othersimilar agents. Suitable disintegrants include starch,polyvinylpolypyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate.

Suitable pharmaceutically acceptable wetting agents include sodiumlauryl sulphate. Oral liquid preparations may be in the form of, forexample, aqueous or oily suspensions, solutions, emulsions, syrups, orelixirs, or may be presented as a dry product for reconstitution withwater or other suitable vehicle before use. Such liquid preparations maycontain conventional additives such as suspending agents, for examplesorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,carboxymethylcellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

Oral liquid preparations are usually in the form of aqueous or oilysuspensions, solutions, emulsions, syrups, or elixirs or are presentedas a dry product for reconstitution with water or other suitable vehiclebefore use. Such liquid preparations may contain conventional additivessuch as suspending agents, emulsifying agents, non-aqueous vehicles(which may include edible oils), preservatives, and flavouring orcolouring agents.

The oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art.

For parenteral administration, fluid unit dose forms are preparedcontaining a compound of the present invention and a sterile vehicle.The compound, depending on the vehicle and the concentration, can beeither suspended or dissolved. Parenteral solutions are normallyprepared by dissolving the compound in a vehicle and filter sterilisingbefore filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are also dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilised by exposure of ethylene oxide before suspendingin the sterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound of the invention.

The invention further provides a method of treatment or prophylaxis ofirritable bowel syndrome, dyspepsia, atrial arrhythmias and stroke,anxiety and/or migraine in mammals, such as humans, which comprises theadministration of an effective amount of a compound of the formula (I)or a pharmaceutically acceptable salt thereof.

An amount effective to treat the disorders hereinbefore describeddepends on the relative efficacies of the compounds of the invention,the nature and severity of the disorder being treated and the weight ofthe mammal. However, a unit dose for a 70 kg adult will normally contain0.05 to 1000 mg for example 0.5 to 500 mg, of the compound of theinvention. Unit doses may be administered once or more than once a day,for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day,that is in the range of approximately 0.0001 to 50 mg/kg/day, moreusually 0.0002 to 25 mg/kg/day.

No adverse toxicological effects are indicated within the aforementioneddosage ranges.

The invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use as an activetherapeutic substance, in particular for use in the treatment ofirritable bowel syndrome, gastro-oesophageal reflux disease, dyspepsia,atrial arrhythmias and stroke, anxiety and/or migraine.

The following Examples illustrates the preparation of compounds offormula (I), and the following Descriptions relate to the preparation ofintermediates.

DESCRIPTION 1

A stirred solution of 8-acetamido-1,4-benzodioxan-5-carboxylic acid (GB1 571 278) (2.5 g, 0.0105 mole)in methanol (60 ml) was treated withconcentrated sulphuric acid (2 ml) and the solution kept at roomtemperature for 20 hours, then concentrated in vacuo to approxiamately10 ml volume. The residue was treated with water (30 ml), basified withpotassium carbonate and a precipitate was produced. This was filteredoff, washed with water and dried to afford methyl8-amino-1,4-benzodioxan-5-carboxylate as a white solid (1.96 g, 89%). ¹H NMR (CDCl₃) δ:7.38(d,1 H), 6.28(d,1 H), 4.25-4.43(m,4 H), 4.12(br s,2H), 3.83(s,3 H).

b) Concentrated sulphuric acid (6.5 ml) was treated cautiously withstirring at 5°-10° C. with glacial acetic acid (12 ml) and to theresulting solution was added methyl8-amino-1,4-benzodioxan-5-carboxylate (1.5 g, 0.0072 mole). The mixturewas stirred at room temperature for 1 h, then treated portionwise over45 minutes with potassium nitrate (0.85 g, 0.0084 mole). The mixture wasstirred for a further 4 h then poured into water (100 ml) and basifiedwith potassium carbonate. A precipitate was produced and this wasfiltered off, washed with water and dried to afford methyl8-amino-7-nitro-1,4-benzodioxan-5-carboxylate as a yellow solid (0.30g). The filtrate was extracted with ethyl acetate and the extract dried(Na₂ SO₄) and concentrated in vacuo to afford a further 1.1 g of theproduct as an orange solid. ¹ H NMR (CDCl₃) δ:8.50(s,1 H), 6.0-7.0(vbr,2 H), 4.30-4.55(m,4 H), 3.87(s,3 H).

c) A stirred suspension of methyl8-amino-7-nitro-1,4-benzodioxan-5-carboxylate (300 mg, 0.0012 mole) inethanol (30 ml) together with glacial acetic acid (5 ml) washydrogenareal over 10% Pd-C (100 mg) at atmospheric pressure andtemperature for 5 h. The catalyst was filtered off and the filtrateconcentrated in vacuo. The residue was basified with concentratedpotassium carbonate solution and extracted with ethyl acetate. Theextract was dried (Na₂ SO₄) and concentrated in vacuo to afford methyl7,8-diamino-1,4-benzodioxan-5-carboxylate as a beige solid (240 mg,92%). ¹ H NMR (CDCl₃) δ:6.91(s,1 H), 4.21(s,4 H), 3.96(br s.2 H),3.74(s,3 H), 3.0(br s,2 H).

d) A solution of methyl 7,8-diamino-1,4-dioxan-5-carboxylate (240 mg,1.07 mmole) in formic acid (15 ml) was heated under reflux for 3 h. Thesolution was concentrated in vacuo and the residue basified withpotassium carbonate solution and a white solid was produced. This wasfiltered off, washed with water and dried to give methyl 1H-7,8-dihydro- 1,4!-dioxino 2,3-g!benzimidazole-5-carboxylate (110 mg,44%). ¹ H NMR (d⁶ DMSO) δ:8.19(s,1 H), 7.55(s,1 H), 4.30-4.45(m,4 H),3.78(s,3 H), 3.6 (v br, 1 H).

DESCRIPTION 2 (1-Butyl-4-piperidinyl)methanol

A mixture of ethyl isonipecotate (102 g, 0.65 mole) and 1-bromobutane(72 ml, 0.67 mole) in ethanol (1.2 L) was treated with anhydrouspotassium carbonate (180 g, 1.3 mole) and heated under reflux for 2 h.The mixture was allowed to cool and then filtered through kieselguhr.The filtrate was concentrated in vacuo to leave a yellow oil, which wasdissolved in ether (300 ml) and added dropwise over 20 minutes to astirred suspension of lithium aluminium hydride (50 g, 1.3 mole) inether (500 ml) at 0° C. under nitrogen. The mixture was stirred at roomtemperature for 18 h, then cooled to 0° C. and treated with water (50ml), 10% NaOH solution (50 ml) and water (150 ml). The mixture wasfiltered through keiselguhr and the filtrate concentrated under vacuumto leave a pale yellow oil, which was distilled to afford the titlecompound (D2) as a colourless oil (88.5 g, 80%) bp 102°-108° C. at 0.1mm Hg. ¹ H NMR (CDCl₃) δ:3.48(d,2 H), 2.88-3.03(m,2 H), 2.25-2.38(m,2H), 2.10(br s, 1 H), 1.66-2.00(m,4 H), 1.17-1.60(m,7 H), 0.90(t,3 H).

EXAMPLE 1 (1-Butyl-4-piperidinyl)methyl 1 H-7,8-dihydro- 1,4!-dioxino2,3-g!benzimidazole-5-carboxylate R₁ 'R₂ =--NH--CH═N--, R₃ =H, R₄ ¹,R₄ ²=H, X₁,X₂ =O, x=2, Y=O, Z=(i)!

A stirred solution of (1-butyl-4-piperidinyl)methanol (D2, 290 mg,0.0017 mole) in THF (20 ml) under argon at 5° C. was treated with 1.5Mmethyllithium in ether (0.67 ml, 0.0010 mole). After 10 minutes thesolution was treated with solid methyl 1 H-7,8-dihydro- 1,4!-dioxino2,3-g!benzimidazole-5-carboxylate (D 1, 100 mg, 0.43 mmole) and heatedunder reflux for 3 h. The mixture was then treated dry with DMF (15 ml)to aid solubility, followed by more methyl 1 H-7,8-dihydro- 1,4!-dioxino2,3-g!benzimidazole-5-carboxylate (200 mg, 0.86 mmole) and(1-butyl-4-piperidinyl)methanol (290 mg, 0.0017 mole) and heated underreflux for 6 h. The mixture was allowed to cool, then concentrated invacuo and the residue treated with 10% Na₂ CO₃ solution and extractedwith chloroform. The extract was dried (Na₂ SO₄) and concentrated invacuo to afford a beige solid, which was washed with n-pentane to removeexcess alcohol and then chromatographed on silica gel eluting with 0-10%methanol/chloroform. The title compound was obtained as a beige solid(60 mg), which was converted to its oxalate salt and crystaIlized fromacetone as a beige solid mp 123°-127° C. ¹ H NMR (CDCl₃) δ:8.15(s,1 H),7.70(s,1 H), 6.5-8.5(v br,1 H), 4.39(m,4 H), 4.18(d,2 H), 3.12(br d,2H), 2.40-2.55(m,2 H), 2.00-2.20(m,2 H), 1.75-1.95(m,3 H), 1.46-1.72(m,4H), 1.20-1.43(m,2 H), 0.91 (t,3 H).

The following compounds are prepared from the corresponding acid andlithium-(1-butyl-4-piperidinyl)methoxide via the imidazolide.

(1-Butyl-4-piperidinyl)methyl 1 H-7,8-dihydropyrano 1,4-g!dioxino2,3-g!carboxylate R₁ --R₂ =--NH--CH═CH--, R₃ ═H, R₄ ¹,R₄ ² =H, X₁,X₂ =O,x=2, Y=O, Z=(i)!

(1-Butyl-4-piperidinyl)methyl 1 H-3,7,8,9-tetrahydropyrano3,2-e!indolecarboxylate R₁ --R₂ =--C═CH--NH--, R₃ =H, R₄ ¹,R₄ ² =H, X₁=O, X₂ =CH₂ x=2, Y=O, Z=(i)!

5-HT₄ RECEPTOR ANTAGONIST ACTIVITY

1) Guinea pig colon

Male guinea-pigs, weighing 250-400 g are used. Longitudinalmuscle-myenteric plexus preparations, approximately 3 cm long, areobtained from the distal colon region. These are suspended under a 0.5 gload in isolated tissue baths containing Krebs solution bubbled with 5%CO₂ in O₂ and maintained at 37° C. In all experiments, the Krebssolution also contains methiothepin 10⁻⁷ M and granisetron 10⁻⁶ M toblock effects at 5-HT₁, 5-HT₂ and 5-HT₃ receptors.

After construction of a simple concentration-response curve with 5-HT,using 30s contact times and a 15 min dosing cycle, a concentration of5-HT is selected so as to obtain a contraction of the muscleapproximately 40-70% maximum(10⁻⁹ M approx). The tissue is thenalternately dosed every 15 min with this concentration of 5-HT and thenwith an approximately equi-effective concentration of the nicotinereceptor stimulant, dimethylphenylpiperazinium (DMPP). After obtainingconsistent responses to both 5-HT and DMPP, increasing concentrations ofa putative 5-HT₄ receptor antagonist are then added to the bathingsolution. The effects of this compound are then determined as apercentage reduction of the contractions evoked by 5-HT or by DMPP. Fromthis data, pIC₅₀ values are determined, being defined as the -logconcentration of antagonist which reduces the contraction by 50%. Acompound which reduces the response to 5-HT but not to DMPP is believedto act as a 5-HT₄ receptor antagonist.

The compound of Example 1 had a pIC₅₀ value of 6.78 (±0.11) (n=4)

We claim:
 1. Compounds of formula (I), or pharmaceutically acceptablesalts thereof: ##STR6## wherein X₁ --(CH₂)_(x) --X₂ and the aromaticcarbon atoms to which they are attached form a 5-7 membered ringX₁ is Oor S; X₂ is O or S; or one of X₁ and X₂ is O, S or CH₂ and the other isCH₂ ; x is 1 or 2; R₁ and R₂ together are Q--CH₂ --CH₂, Q--CH═CH, orQ--CH═N where Q is linked either to the R₁ or the R₂ substitutionposition and Q is O, S or NR_(t) wherein R_(t) is hydrogen or C₁₋₆alkyl; R₃ is hydrogen, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy or amino; R₄ ¹ andR₄ ² are independently hydrogen or C₁₋₆ alkyl; Y is O or NH; Z is ofsub-formula (a): ##STR7## wherein n¹ is 1, 2, 3 or 4; q is 0, 1, 2 or 3;R₅ is hydrogen, C₁₋₁₂ alkyl, aralkyl or R₅ is (CH₂)_(z) --R₁₀ wherein zis 2 or 3 and R₁₀ is selected from cyano, hydroxyl, C₁₋₆ alkoxy,phenoxy, C(O)C₁₋₆ alkyl, COC₆ H₅, --CONR₁₁ R₁₂, NR₁₁ COR₁₂, SO₂ NR₁₁ R₁₂or NR₁₁ SO₂ R₁₂ wherein R₁₁ and R₁₂ are hydrogen or C₁₋₆ alkyl; or R₅ isstraight or branched chain alkylene of chain length 1-6 carbon atomsterminally substituted by aryl, 3 to 8 membered cycloalkyl, 3 to 8membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl or 9 or 10membered fused bicyclic heteroaryl linked through carbon, C₂₋₇alkoxycarbonyl, or secondary or tertiary hydroxy substituted C₁₋₆ alkyl;and R₆ is hydrogen or C₁₋₆ alkyl; or a compound of formula (I) whereinthe CO--Y linkage is replaced by a heterocyclic bioisostere.
 2. Acompound according to claim 1 wherein R₁ and R₂ are joined to form--NH--CH═N--.
 3. A compound according to claim 1 wherein the moietyattached to CO--Y--Z in formula (I) is wherein:R₁ --R₂ are together--NH--CH═N--, R₃ is H, R₄ ¹ and R₄ ² are H, X₁ and X₂ are O, and x is 2;R₁ --R₂ are together --NH--CH═CH--, R₃ is H, R₄ ¹ and R₄ ² are H, X₁ andX₂ are O, and x is 2; or R₁ --R₂ are together --C═CH--NH--, R₃ is H, R₄¹ and R₄ ² are H, X₁ is O, X₂ is CH₂, and x is
 2. 4. A compoundaccording to claim 1 wherein Z is of sub-formula (a) and (CH₂)_(n) 1 isattached at a carbon atom of the azacycle.
 5. A compound according toclaim 4 wherein Z is N-substituted 4-piperidinylmethyl.
 6. A compoundaccording to claim 5 wherein the N-substituent is C₂ or greater alkyl,or optionally substituted benzyl.
 7. A compound according to claim 1wherein Y is NH.
 8. (1-Butyl-4-piperidinyl)methyl 1 H-7,8-dihydro-1,4!-dioxino 2,3-g!benzimidazole-5-carboxylate.
 9. A pharmaceuticalcomposition comprising a compound according to claim 1, and apharmaceutically acceptable carrier.
 10. A method of treatinggastrointestinal disorders or cardiovascular disorders which comprisesadministering an effective amount of a compound according to claim 1.11. A method of treating migraine, anxiety, schizophrenia, Parkinson'sdisease and Huntington's chorea which comprises the administering aneffective amount of a compound according to claim
 1. 12. A method oftreating atrial arrhythmia or stroke which comprises administering aneffective amount of a compound according to claim
 1. 13. A method oftreating urinary incontinence which comprises administering an effectiveamount of a compound according to claim
 1. 14. A method of treatingirritable bowel syndrome which comprises administering an effectiveamount of a compound according to claim 1.